Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs, and NF-kappaB. Am J Physiol Gastrointest Liver Physiol 2009 Feb;296(2):G388-98
Date
12/17/2008Pubmed ID
19074641DOI
10.1152/ajpgi.90428.2008Scopus ID
2-s2.0-59449103458 (requires institutional sign-in at Scopus site) 82 CitationsAbstract
Human esophageal epithelial cells play a key role in esophageal inflammation in response to acidic pH during gastroesophageal reflux disease (GERD), increasing secretion of IL-6 and IL-8. The mechanisms underlying IL-6 and IL-8 expression and secretion in esophageal epithelial cells after acid stimulation are not well characterized. We investigated the role of PKC, MAPK, and NF-kappaB signaling pathways and transcriptional regulation of IL-6 and IL-8 expression in HET-1A cells exposed to acid. Exposure of HET-1A cells to pH 4.5 induced NF-kappaB activity and enhanced IL-6 and IL-8 secretion and mRNA and protein expression. Acid stimulation of HET-1A cells also resulted in activation of MAPKs and PKC (alpha and epsilon). Curcumin, as well as inhibitors of NF-kappaB (SN-50), PKC (chelerythrine), and p44/42 MAPK (PD-098059) abolished the acid-induced expression of IL-6 and IL-8. The JNK inhibitor SP-600125 blocked expression/secretion of IL-6 but only partially attenuated IL-8 expression. The p38 MAPK inhibitor SB-203580 did not inhibit IL-6 expression but exerted a stronger inhibitory effect on IL-8 expression. Together, these data demonstrate that 1) acid is a potent inducer of IL-6 and IL-8 production in HET-1A cells; 2) MAPK and PKC signaling play a key regulatory role in acid-mediated IL-6 and IL-8 expression via NF-kappaB activation; and 3) the anti-inflammatory plant compound curcumin inhibits esophageal activation in response to acid. Thus IL-6 and IL-8 expression by acid may contribute to the pathobiology of mucosal injury in GERD, and inhibition of the NF-kappaB/proinflammatory cytokine pathways may emerge as important therapeutic targets for treatment of esophageal inflammation.
Author List
Rafiee P, Nelson VM, Manley S, Wellner M, Floer M, Binion DG, Shaker RAuthor
Reza Shaker MD Assoc Provost, Sr Assoc Dean, Ctr Dir, Chief, Prof in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnthracenesAnti-Inflammatory Agents
Benzophenanthridines
Cell Line
Curcumin
Enzyme Activation
Epithelial Cells
Esophagus
Flavonoids
Humans
Hydrogen-Ion Concentration
Imidazoles
Interleukin-6
Interleukin-8
Mitogen-Activated Protein Kinases
Mucous Membrane
NF-kappa B
Peptides
Protein Kinase C
Protein Kinase Inhibitors
Pyridines
Signal Transduction
Telomerase
Time Factors
Transcription, Genetic
Up-Regulation